Autism spectrum disorder (ASD) refers to a group of heritable neuropsychiatric disorders whose symptoms, which include deficits in social interaction skills, impaired communication ability, and ritualistic-like repetitive behaviors, appear in early childhood and continue throughout life. In particular, repetitive, stereotyped and perseverative behaviors cause severe disruptions in the quality of life of ASD individuals and their families. Despite their clinical importance, the studies concerning these behaviors are relatively small in comparison with the investigations of other aspects of ASD symptomatology. Consequently, there is a significant need to understand the pathophysiology of these motor disturbances and the establishment of mechanism-based therapeutics to treat repetitive behaviors. The goal of this research proposal is to study how altered structural and synaptic plasticity in the striatum leads to repetitive, stereotyped and perseverative behaviors, and to identify new molecular targets to develop mechanism-based therapeutics to treat ASD. The central hypothesis of this proposal is that exaggerated cap-dependent protein synthesis in striatal medium spiny neurons (MSNs) causes altered plasticity resulting in repetitive, stereotyped, and perseverative behaviors. The novel eIF4E transgenic mouse (eIF4E Tg) model of ASD will be utilized to address three specific aims. Aim 1 will be performed during the mentored phase (K99) and is to determine whether eIF4E Tg mice display alterations in structural and synaptic plasticity in a specific subset of striatal medium-sized spiny neurons (MSNs). The remaining two aims will be initiated during the mentored phase (K99) and will be completed during the independent phase (R00). Aim 2 is to determine whether increased expression of eIF4E restricted to a specific subset of striatal MSNs is necessary and sufficient to generated ASD-like motor behavior. Aim 3 is to determine the identity of proteins whose synthesis is altered in a specific subset of striatal MSNs in the eIF4E transgenic mice. Lack of understanding of ASD pathogenesis hampers our search for new mechanism-based targets. This proposal will provide insight into how abnormal striatal synaptic physiology contributes to ASD etiology and molecular targets for the design of novel therapeutics for ASD.